Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real‐world intention‐to‐treat analysis

Abstract Brexucabtagene autoleucel (brexu‐cel) is an autologous CD19 CAR T‐cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA‐2, brexu‐cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real‐world intention‐to‐treat (ITT) outcomes for brexu‐cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu‐cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow‐up of 13.3 months, median progression‐free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6‐ and 12‐month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non‐relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA‐2 and other real‐world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention.


INTRODUCTION
Mantle cell lymphoma (MCL), accounting for 3%-6% of non-Hodgkin lymphoma (NHL), 1 is a rare disease marked by significant clinical and pathological heterogeneity. 2 While a subset of patients, particularly those with leukemic, non-nodal variant, may initially exhibit features of indolent disease, MCL is usually aggressive with the majority of patients eventually requiring treatment.Disease risk profile is guided by factors such as the MCL international prognostic index (MIPI), 3 response to frontline therapy, proliferation index (Ki-67%), 4 blastoid/ pleomorphic subtypes 5 and genetic aberrations such as TP53. 6][10][11] Chimeric antigen receptor (CAR) T-cell therapy represents a new therapeutic option for eligible patients with relapsed refractory (r/r) MCL.The Phase 2 nonrandomised ZUMA-2 study demonstrated a high initial overall response rate (ORR) of 93% with a complete response (CR) rate of 67% with brexucabtagene autoleucel (brexu-cel) in r/r MCL. 12 At a median follow-up of 35.6 months, median progression-free survival (PFS) and overall survival (OS) were 25.8 and 46.6 months, respectively and 37% of patients were in remission without further therapy. 12,13In December 2020 the European Medicines Agency (EMA) granted conditional marketing authorization for brexu-cel (Kite Gilead) in r/r MCL after ≥2 lines of therapy, including a bruton's tyrosine kinase inhibitor (BTKi).5][16] Disease-specific features associated with an inferior PFS include high simplified MIPI score, 15,16 Ki-67 ≥ 50%, complex karyotype, TP53 aberration, and blastoid/pleomorphic variant. 16However, rates of non-relapse mortality (NRM) are significantly higher in the real-world relative to ZUMA-2 (3%), ranging from 9% to 15%, [15][16][17] with a signal for late fatal infectious events.Identification of those most likely to benefit and an understanding of late toxicities are key to appropriate patient selection and tailored care post-infusion.
Herein, we present our intention-to-treat (ITT) real-world outcomes for brexu-cel in the United Kingdom (UK) with a focus on feasibility, efficacy and tolerability in those with r/r MCL after a BTKi.

Patients
Consecutive patients with r/r MCL, prospectively approved by the National CAR T Clinical Panel (NCCP), from 12 CAR T centres in England (or Scottish equivalent) between February 2021 and June 2023 were included (Table S1) (intention-to-treat cohort).The UK NCCP approval process has been previously described 18 and data were extracted retrospectively from electronic records as part of a national service evaluation.Eligibility for treatment required ECOG PS of 0 or 1, absence of active central nervous system (CNS) disease and ≥2 lines of therapy including prior BTKi 19 (Table S2).Organ function requirements were at the discretion of the treating centre.

Definitions
Pre-apheresis bridging therapy (BT) was defined as any lymphoma therapy delivered between NCCP approval and T-cell apheresis.Postapheresis BT was defined as any lymphoma therapy delivered between T-cell apheresis and admission for CAR T. All BT was administered at discretion of the treating physician.Manufacturing failure (MF) was defined as failure of the leukapheresis material to successfully yield a CAR T cell product that could be requested by the CAR T physician.Out of specification (OOS) products were defined as those that failed to reach release specifications but could be requested and infused at physician discretion.Lymphodepletion (LD) with fludarabine and cyclophosphamide was administered as per manufacturers' instructions.Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) consensus guidelines. 20Toxicity management strategies were at the discretion of the treating centre.Infection was defined as positive microbiology, virology, histopathology, and/or radiological findings as determined by the treating physician and considered alongside clinical symptoms.Culture-negative neutropenic fever was excluded.Grades of infection were categorized as mild (no treatment or oral antibiotics), severe (requiring intravenous therapy), or life-threatening (symptoms such as hemodynamic instability or requiring organ support). 21,22Cumulative steroid dose was reported as dexamethasone equivalent (mg).Response to CAR-T therapy was determined locally (Lugano classification 2014). 23

Statistical analyses
All analyses, graphs, and figures were performed and generated using Stata version 18.0, respectively.Progression-free and overall survival were calculated separately from approval, apheresis, and infusion and were analysed using Kaplan-Meier survival analysis.Patients who did not have an event were censored at the date last seen.Cox proportional hazards models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) in both univariate and multivariable analysis (UVA; MVA).To avoid overfitting, MVA utilised a backward stepwise selection method (p = 0.05 for inclusion).NRM, measured from infusion until death without progression (disease progression treated as competing event), was analysed using a competing risks regression model by the method of Fine and Gray to estimate subhazard ratios (SHRs) and corresponding 95% CIs.Odds ratios, corresponding 95% CIs, and p-values were estimated using logistic regression.Fisher's exact tests were used when the odds ratio could not be calculated.No adjustments have been made to account for multiple testing.

Failure to reach cell harvest and/or infusion
Seventy percent and 80% of approved and harvested patients, respectively were infused (Figure 1).Progressive disease (PD) was the most common reason for failure to reach cell harvest (9/15, 60%) and cell infusion (18/36, 50%).Where PD was cited as the primary reason for drop out, factors associated with higher rates of drop out included younger age and LDH > upper limit of normal (ULN).ECOG PS > 0 and the presence of extra-nodal disease trended toward significance (Table S3).Other disease-specific features such as TP53 mutation and blastoid disease were not found to be significant.MF with subsequent PD accounted for failure to reach cell infusion in 7/21 cases of drop out post-T-cell harvest (33%).MF occurred in 17/104 harvests (16.3%), with two MFs in two cases.Seven patients (41.2%) were not re-harvested due to PD, one was referred for allograft and one was enrolled on a clinical trial.The remaining eight patients (47%) were infused after a second successful manufacture.On UVA, patients with circulating disease at T-cell harvest were at higher risk of MF (odds ratio [OR]: 2.90, 95% CI 0.95-8.84,p = 0.06), particularly those with high burden in the peripheral blood.Of those with a lymphocyte count of >30 × 10 9 /L in peripheral blood on the day of harvest (n = 6), 75% (n = 4) had a failed first manufacture.Those with LDH > ULN had four times the odds of having a failed manufacture (OR: 4.01 (95% CI: 1.18-13.61,p = 0.03) (Table S4).There was no association between MF and CD3 + cell count in peripheral blood, total CD3 + cells harvested, number of lines of therapy, prior autograft/ allograft, use of pre-apheresis BT or Bendamustine exposure/timing (Table S4).Contrary to drop out due to PD which remained static between 2021 and 2023, the frequency of MF decreased over time (23% of harvests 2021 and 11% of harvests 2022) with no MFs at data cut-off in 2023.Two OOS products were reported, one with a lower transduction efficiency (infused) and one with a visible particle on inspection of final product (re-harvested).

BT
Of approved patients, pre-apheresis BT was administered to 56% (66/119) after approval and before T-cell harvest (at physician discretion).In 49% (32/66), this therapy consisted of continuation of BTKi and/or steroids and/or Rituximab; the remainder receiving mostly R-chemoimmunotherapy (Table S5).Ninety percent (94/104) of patients received BT after T-cell harvest (Table S5).Forty-six percent and 26% were bridged with chemoimmunotherapy and targeted therapy alone, respectively.Nineteen percent (

Response and survival outcomes
Eighty-three patients were evaluable for response; best ORR was 87% (81% CR and 6% PR).PFS and OS from approval, harvest, and infusion are demonstrated in Table S9, Figures 3A-C and 4A-C.Median PFS for all infused patients was 21 months (10.1-NA) with a 6-and 12-month PFS of 82% (71-89) and 62% (49-73), respectively.Median OS was not reached for infused patients with 6-and 12-month OS of 87% (76-93) and 74% (62-83), respectively (Table S9 and Figure 4C).Factors at submission associated with an inferior PFS included male sex, bulky disease >5 cm, and POD24 (Table S7).On MVA, bulky disease and male sex retained significance for both PFS and OS (Table S10).Factors pre-LD associated with an inferior PFS included ≥3 EN sites and ECOG PS > 1 (Table S7).On MVA of pre-LD variables, PFS and OS were independently associated with male sex, ECOG PS > 1 and a previous MF (Table S11).Post-infusion, the occurrence of any grade CRS or ICANS had a protective survival benefit (Table S7).
Eight patients were infused after a 1st MF and a subsequent successful second T-cell harvest.Early relapses were noted in this group with a median PFS of 7.4 months (95% CI: 1.1-NA) relative to a median PFS of 21 months (10.1-NA) in non-MF cohort (Figure 5A,B and Table S12).However, 50% of those with a previous MF remained in remission at month 12 suggesting that some can still derive benefit from this therapy.Survival outcomes for those with MF who did not reach cell infusion were dismal with a median OS of 1.8 months from apheresis (95% CI: 1.1-6.8)(Figure 6A,B).

DISCUSSION
Brexu-cel offers the potential for prolonged remissions in a subset of patients with r/r MCL after failure of BTKi, a particularly poor prognostic group.However, real-world application of CAR T at 3rd  line faces inherent challenges.Considering ITT, 30% of eligible and 20% of harvested patients did not receive their CAR T-cell infusion, with PD the primary cause of drop-out.Historically, a substantial proportion of MCL patients did not go on to receive further therapies after BTKi failure; 57% and 37.9% in the United Kingdom 9 and SCHOLAR-2 11 datasets respectively, with a dismal median OS of 0.4 months.Relative to diagnostic disease risk profiles, a predominance of blastoid phenotype, bulky disease, Ki-67 > 30%/ > 50% and ECOG ≥ 2 have been demonstrated post BTKi failure. 11This mirrors many of the disease features noted among those unfit for further therapy thereafter. 9Where data were available, 38%, 38%, and 76% of our patients had blastoid/ pleomorphic disease, a TP53 mutation and Ki-67 ≥ 30% at submission, respectively.The frequent use of pre-apheresis BT, including chemoimmunotherapy, to stabilize disease after approval also highlights the burden and kinetics of disease at relapse.Taken together, we can hypothesize that MCL patients relapsing on a BTKi in the real-world are challenged by high-risk disease features, rapid disease kinetics, and/or frailty.
Capturing patients failing 2nd line BTKi prior to florid relapse may improve the feasibility and outcome of CAR T treatment, particularly in high-risk candidates.Bulky disease (>5 cm) at submission was independently associated with inferior PFS and OS post-infusion in our cohort.Disease burden variables at submission such as higher LDH and circulating disease were also associated with a higher risk of drop out and MF, respectively.Repeat biopsies at the point of submission for CAR T were not performed in all cases.MCL subtype and TP53 mutation status were unknown at submission in 34% and 53% of patients, respectively and the risk of drop out associated with specific high-risk features therefore cannot be estimated.With a view to improving outcomes, British Society of Haematology (BSH) guidance proposes a risk-based surveillance strategy, for potential CAR T candidates commencing ibrutinib at 2nd line. 19Predictors for shorter PFS on ibrutinib such as disease bulk ≥5 cm, high-risk sMIPI score, POD24, TP53 mutations, and blastoid histology are considered highrisk, [24][25][26] warranting an early response assessment on BTKi and referral to a CAR T centre at the first sign of ibrutinib failure.Of note, the marketing authorization for brexu-cel differs between the EMA and FDA, where exposure to a BTKi is not a requirement for the latter.2nd line CAR T trials should also be explored.
The use of post-apheresis BT is associated with high-risk disease features in large B-cell lymphoma (LBCL) 27,28 but has the potential to stabilize disease and maintain performance status prior to infusion, without compromising outcome. 27Achieving a CR or PR to BT in LBCL has been shown to confer an independent survival benefit, reducing the risk of death or progression post CAR T by 42%. 29BT practice is also supported by the correlation between tumor burden pre-infusion and the risk of higher-grade toxicity 30 and early relapse. 18,31In ZUMA-2, BT was limited to a BTKi and/or steroids and administered to 37% of patients.6][17] Ninety percent of our patients received post harvest therapy achieving an ORR of 41%, with 19% of patients receiving >1 modality of BT.No association between BT response and outcome was noted.However, akin to LBCL, variables such as bulk, EN sites, and ECOG PS > 1 were associated with inferior survival outcomes, inferring the potential for improvement with effective BT strategies.Agents such as pirtobrutinib, venetoclax, and bispecific antibodies are not readily available in the United Kingdom outside of clinical trials.Pirtobrutinib, as a single agent, has demonstrated an ORR of 57.8% in those previously exposed to a covalent BTKi 32 and may be a promising and well-tolerated BT option.
At 16.3%, the rate of MF in our cohort was significantly higher than in ZUMA-2 (4%), 12 United States 16 (3.7%),and European 15 (8%) real-world data sets.The definition of MF can vary, often including out of specification (OOS) products.In our cohort, MF was defined as failure of the leukapheresis material to successfully yield a CAR T-cell product that could be requested by the CAR T physician and was considered separately to OOS.There was no association between MF and CD3 + cell count in peripheral blood, total CD3 + cells harvested, number of lines of therapy, or Bendamustine exposure/timing.On UVA, MF was associated with features of disease burden, including LDH > ULN and circulating disease in the peripheral blood on the day of harvest.In the absence of detailed quantitative and qualitative analysis of the harvested material, 33 these findings are potentially suggestive of a disease-associated qualitative T-cell defect hampering cell expansion during manufacture.Wang et al. have previously demonstrated that T-cells in the MCL tumor microenvironment (TME) demonstrate decreased expression of activation markers with parallel increased expression of markers associated with exhaustion and senescence, 34 a well-recognized phenomenon in cancer. 35Although, the manufacture of brexu-cel encompasses a T-cell selection step to remove contaminating cells from the harvest material, it is conceivable that circulating MCL cells in the peripheral blood, namely the TME, may contribute to inherent T-cell dysfunction and failure of expansion during manufacture in such patients.Other groups have demonstrated that MF rates are higher in those who have received Bendamustine. 16,36,37Only one patient with MF had received Bendamustine within 6 months of harvest.Acknowledging small numbers, no association between Bendamustine and MF was found.Outcomes for patients with B-cell malignancies receiving OOS CAR T products appear comparable to those with compliant products. 36,38,39owever, on MVA in our cohort, PFS outcomes for those with ≥1 MF, who were subsequently infused after a second successful manufacture (n = 8), were inferior with a shorter median PFS of 7.4 months (95% CI: 1.1-NA) relative to a median PFS of 21 months (10.1-NA) in the non-MF cohort.This may be indicative of poor persistence and T-cell functionality in this subset.Although 50% remained in remission at 1 year post-infusion, consolidative therapies could be considered in appropriate high-risk candidates.Longer follow-up and larger numbers are needed to assess durability of response and the contributing factors in such patients.The lower incidence of MF in 2022/23 may be related to an initial backlog of high-burden patients in the first year of drug approval and/or emerging early data on the potential importance of disease control at cell harvest. 40urvival outcomes for patients infused with brexu-cel in the United Kingdom are comparable to those achieved in ZUMA-2 12 and larger real-world datasets. 15,16Relatively poorer survival outcomes have been reported by other groups, 41,42 although short follow-up and small numbers preclude firm conclusions.In our cohort, neither the use of Bendamustine prior to harvest nor the presence of high-risk disease features such as TP53 mutation, blastoid disease, high-risk sMIPI score or Ki-67 ≥ 50% were associated with an inferior PFS or OS.On MVA, bulky disease at submission, male sex, ECOG PS > 1 pre-LD, and MF had a negative impact on survival.Of note, our survival outcomes diverge from ZUMA-2 and other real-world reports when we consider all patients initially proposed for brexu-cel; our ITT cohort had a median PFS of 11.4 months (Table S9), highlighting the challenges of real-world delivery.This may be reflective of how trial logistics with strict eligibility criteria can exclude the most representative sample of candidates.Consideration of ITT outcome is important as we counsel our patients and assess the risk: benefit of brexu-cel compared to newer targeted treatments competing for the 3rd line MCL space.With the advent of CAR T therapy for MCL, allograft has fallen out of favor.ASTCT, CIBMTR, and EBMT guidance currently recommends consideration of CAR T over allograft, where CAR T is available 43 (Grade C Recommendation).A higher rate of drop out in younger patients in our cohort conflicts somewhat with data in LBCL, where ASCT-unfit patients, a predominantly older cohort, were less likely to reach cell infusion. 44It raises questions on the role of allograft in select younger fit candidates with high-risk disease in first remission or responding to a covalent BTKi.In the absence of more effective bridging strategies, rapid refractory PD post-BTKi failure is a concern, and feasibility of CAR T treatment at 3rd line cannot be guaranteed.
Although rates of high-grade CRS, ICANS, and infection were inkeeping with the expected toxicity profile of brexu-cel, extended follow-up of our cohort demonstrated a cumulative incidence of NRM of 6%, 15%, and 25% at 6 months, 1, and 2 years, respectively.The HEMATOTOX (HT) score has been shown to delineate those at higher risk of NRM, severe infections, and haematotoxicity post-brexu-cel. 17n our analysis, risk factors for NRM included older age, male sex, LDH > ULN, and severe or life-threatening infection with 1 month of infusion.The excess of late NRM events (>90 days, 58%) is of concern, F I G U R E 6 (A, B) Progression-free survival outcome (A) and overall survival outcome (B) for all patients harvested with/without manufacturing failure.Note that the groups should not be directly compared as they are defined by events that occur at different points after the date of apheresis.For example, patients who had manufacturing failure and subsequent infusion must have had stable disease for long enough to undergo a second apheresis and receive the infusion to be counted in that group.
with SARS-CoV2 accounting for 43% (3/7).Despite the reduced incidence of SARS-CoV2-related mortality in recent years (likely attributable to the combination of less virulent variants, vaccination programs, and pre-emptive pharmacotherapies), this group remain vulnerable. 45Vaccine-induced T-cell responses may provide some protection to those with B-cell aplasia and impaired antibody production. 46Older patients are at higher risk of NRM, despite a preserved ECOG PS pre-LD (Tables S7 and S8), suggesting that more sensitive measures of "fitness" may be required.Distinct from age and ECOG PS, frailty is defined as a state of increased vulnerability or lower resilience in response to acute stressors and is associated with adverse outcomes. 47There are limited data on frailty and the rehabilitation needs of older CAR T patients (pre-infusion and post-infusion) but there is increasing awareness of this clinical need. 48Given the median age at diagnosis of MCL is 68 years and the majority of those failing ≥2 lines of therapy will be >70 years, rigorous patient selection is a key component of harnessing the benefits of this CAR T product.Close observation for (and investigation of) late haematotoxicity, including early consideration of a stem cell boost where appropriate, adherence to prophylaxis guidance, use of intravenous immunoglobulin, and post-CAR T vaccination are important components in maintaining longerterm safety post-infusion. 49,50Lisocabtagene maraleucel (Liso-cel), recently licensed by the FDA, has demonstrated durable responses with a more favorable toxicity profile in a similar cohort of patients 51 and may represent an alternative option in less robust candidates.
Our ITT analysis is limited by retrospective data collection (despite prospective patient approval), somewhat limited repeat biopsies at submission, lack of central response assessment, and of pharmacokinetic data.Eligibility for ZUMA-2 was not assessed.Data on the impact of manufacturing/harvest slot availability and physician decision to give apheresis BT were not recorded.Our analysis also assumes that physicians adhered to recommended drug washout periods prior to T-cell harvest.Although exact cell delivery dates were not recorded, median time from harvest to infusion in our cohort was 36 days.UK turnaround times are therefore longer than ZUMA-2 12 (median of 16 days to cell delivery) but comparable to United States 16 (median of 28 days to LD) and European 15 (median of 41 days to infusion) real-world data sets.
In summary, brexu-cel can achieve high response rates and durable remissions in a subset of MCL patients after ≥2 lines of therapy.ITT analysis highlights that a significant proportion of eligible patients fail to reach cell infusion due to PD or MF.Detection of early failure of ibrutinib and more effective bridging strategies will be key factors in reducing drop out and improving survival outcomes.NRM events, early and late, warrant further attention.

F
I G U R E 4 (A-C) Overall survival (OS) from approval (A), apheresis (B), and infusion (C) by Kaplan-Meier analysis.F I G U R E 5 (A, B) Progression-free survival outcome (A) and overall survival outcome (B) for infused patients with/without manufacturing failure.
Baseline characteristics of mantle cell lymphoma patients.
Toxicity profile of brexu-cel and toxicity management strategies.